Inhibiting cancer's spread

Sept. 2, 2004

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By BARBARA BERG

Dr. Olga Klezovitch, right, and graduate student John Chevillet co-led a study that discovered a protein that drives the spread of prostate cancer.

Photo by Todd McNaught

When cancer spreads from its original location to other parts of the body, it becomes much more deadly. Survival rates plunge dramatically. Now, by uncovering a key driver of this dangerous progression in prostate cancer, scientists in the Human Biology Division have made a discovery that may spawn new treatments to prevent cancer's spread and extend patients' survival.

The study, conducted by Dr. Valeri Vasioukhin's laboratory, appears as the cover story of the August issue of Cancer Cell. Dr. Olga Klezovitch, staff scientist, and John Chevillet, a Molecular and Cellular Biology graduate student, co-led the analysis, which also involved collaborators at Vanderbilt University.

The work focused on a protein called hepsin, which has been found in high levels in human prostate and ovarian tumors. In the study, Vasioukhin and colleagues examined what would happen if hepsin were overproduced in mice that had non-progressing forms of prostate cancer. They found that hepsin caused cells in the prostate tumor to lose their grip from the surrounding tissue and to spread from the prostate to bone, lung and liver.

Hepsin is a type of enzyme known as a protease. Drugs to inhibit proteases produced by HIV have been used extensively to thwart the progression of AIDS. This fact, combined with hepsin's specific role in cancer progression, makes it a highly promising drug target, Vasioukhin said.

"Because hepsin is a protease — and proteases are relatively easy to inhibit — we think it will be possible to develop an inhibitor of hepsin that prevents metastasis," he said. "Previous research has demonstrated that hepsin is not critical for normal cells within the body and, therefore, hepsin inhibitors that are very specific would be unlikely to have significant side effects."

In collaboration with the laboratory of Dr. Julian Simon in the Human Biology and Clinical Research divisions, Vasioukhin's lab plans to search for small molecules that can inhibit hepsin.

"We are hoping that highly specific hepsin inhibitors can be used in the future to block or slow down the progression of prostate cancer from relatively harmless benign tumor to highly advanced metastatic disease."

Metastasis reduces survival

Metastasis — the spread of cancer from its site of origin to another location in the body — is a condition that can dramatically reduce a patient's chances for survival. The majority of prostate cancers are diagnosed while the disease is still confined to the prostate, a stage at which five-year survival rates are nearly 100 percent. In contrast, when the disease has spread to distant parts of the body — commonly to the bone — only about one-third of patients survive five years.

While doctors have dramatically improved survival rates for prostate cancer through earlier diagnosis, there remains a need for effective therapies for men whose disease is advanced, said Dr. Pete Nelson, a Human Biology Division investigator and a physician who treats prostate-cancer patients.

"If hepsin indeed drives metastasis in human prostate cancer and if inhibitors of hepsin can be identified, it could offer new options for patients whose disease has spread," he said. "Alternatively, hepsin activity could be exploited to activate pro-drugs (precursors of chemotherapeutic drugs that are toxic to cells) locally in the tumor environment where the protease is produced at high levels. This approach could spare normal tissues that produce the enzyme at low levels."

A large family of enzymes, proteases are found in all animals. Some proteases play an important role in ensuring that cells are organized correctly within a tissue or organ. For example, cells that can give rise to prostate cancer must adhere to a scaffold-like structures, called basement membranes, that keep distinct layers of cells separated from one another.

To examine the consequences of excess amounts of hepsin, Vasioukhin's group developed a strain of mice that produced elevated amounts of hepsin in the prostate gland. The mice with elevated hepsin levels had defects in the basement membrane that separates different populations of cells. This finding was interesting because disorganization and disruption of the basement membrane is a mandatory step that occurs in early phases of metastasis.

Next, the researchers bred these mice with ones that develop a form of prostate cancer that does not metastasize. This generated cancer-susceptible mice that overproduce hepsin. They found these mice developed more advanced prostate tumors and metastases in the liver, lung and bone. These data provide strong evidence that hepsin promotes prostate cancer progression and metastasis.

Vasioukhin said that hepsin is not normally produced in the mouse prostate. Hepsin overproduction was not observed in other mouse models of prostate cancer.

"One simplified way to explain our observations in mice is that overproduction of hepsin is what's necessary to drive prostate cancer metastasis to the bone," he said.

Although the absence of hepsin may prevent metastasis, Vasioukhin said studies from human cancers suggest that very high levels might also prevent cancer from spreading.

"There have been controversial results about hepsin levels in human cancer," he said. "It may be that the change from very low levels to elevated levels of hepsin will promote metastasis. But in a few cases when the levels are too high, it may cause enough disruption to the cell's gripping abilities so that they can't form new attachments at sites in the body distant from the original tumor."

In addition to searching for inhibitors of hepsin, Vasioukhin's lab also plans to study mechanisms of hepsin function in prostate-cancer metastasis. Specifically, the researchers will try to determine how hepsin causes disorganization of the basement membrane.

Research in Vasioukhin's lab is funded by the V Foundation for Cancer Research and the National Cancer Institute.